Despite intensive investigation the immune responses necessary for control of, and protection against HIV infection remain unknown. While potent adaptive T and B cell responses are mounted against HIV and SIV, they do not emerge until after massive virus dissemination and CD4+ T cell loss has already occurred. HIV/SIV infections also break down the integrity of the gastrointestinal mucosa and lead to chronic immune activation that drives disease progression. Recent data from our laboratory and others have identified the macaque counterpart to Type 3 mucosae-restricted innate lymphoid cells (ILCs), distinguishable by high expression of NKp44 and ROR?t. Although ILCs play key roles in mucosal defense and homeostasis, the full functional repertoires of these cells remain to be elucidated, and whether these cells could mount antiviral immune responses against lentiviruses remains unclear, in part because these cells remain very poorly characterized. Interestingly, ILCs are depleted very early from the gastrointestinal tract following SIV infection and ILCs, which are normally noncytolytic, dramatically upregulate cytotoxic functions during infection. This could suggest subversion of ILCs by the virus may facilitate transmission and disease progression. In this new proposal we will address major deficits to this new field of study by utilizing a new anti-NKp44 ILC-depleting antibody. We will evaluate the overarching hypothesis that NKp44+ ILCs modulate gut homeostasis and immune activation, and depletion will exacerbate SIV transmission and dissemination. We will evaluate this hypothesis with two focused Specific Aims: (1) Define the kinetics, activation, and detailed immunologic effects of anti-NKp44 administration in normal rhesus macaques; and (2) Investigate the effects of ILC depletion on SIV transmission, dissemination, and disease following challenge.